Clopidogrel + ASA for afib: fewer strokes, more hemorrhages (ACTIVE)

Clinical Question

Is clopidogrel plus aspirin more effective than aspirin alone for patients with atrial fibrillation who do not take warfarin?

Bottom Line

Clopidogrel (Plavix) plus aspirin provides a small reduction in disabling stroke (number needed to treat [NNT] = 200 per year), but causes an increased risk of major hemorrhage (number needed to treat to harm [NNTH] = 143 per year). At a cost of approximately $1000 per year for clopidogrel, the cost to prevent a single disabling stroke is $200,000, although presumably preventing a disabling stroke will reduce the subsequent costs of care for that person. A cost-effectiveness analysis is needed to determine whether this modest net benefit is worth the cost. (LOE = 1b)


ACTIVE investigators, Connolly SJ, Pogue J, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009;360(20):2066-2078.  [PMID:19336502]

Study Design

Randomized controlled trial (double-blinded)






Outpatient (any)


Patients with atrial fibrillation at high risk for stroke generally receive warfarin, and those at lower risk receive aspirin. The manufacturers of clopidogrel would like to suggest a third option: clopidogrel plus aspirin. In the first ACTIVE study, they found that warfarin was better than this combination in patients with at least 1 risk factor for stroke who were willing to consider taking warfarin (Lancet 2006;367:1903-1912; POEM 80843). Risk factors for stroke were: at least 75 years old, previous stroke or transient ischemic attack [TIA], previous non-CNS embolism, peripheral vascular disease, heart failure, diabetes mellitus, or coronary artery disease. In the current study, a second group of patients who also had at least 1 risk factor for stroke but did not want to take warfarin were randomized to receive clopidogrel 75 mg once daily plus aspirin 75 mg to 100 mg once daily or aspirin alone. Patients with thrombocytopenia, alcohol abuse, recent peptic ulcer disease, or previous intracerebral hemorrhage were excluded. The mean age of participants was 71 years, most had a CHADS2 score of 1, 2, or 3 points, suggesting low to moderate risk of stroke. Most had persistent or permanent atrial fibrillation, and only 13% had experienced a previous stroke or TIA. The reasons they chose not to take warfarin included bleeding risk (23%), physician judgment (51%) and patient preference (26%). Patients were followed up for a median of 3.6 years. The primary outcome was a combination of any major vascular event (stroke, embolism, myocardial infarction, or vascular death), and was less common in patients taking the combination therapy than in those taking the aspirin alone (6.8% vs 7.6% per year; P = 0.01; NNT = 125). Looking more closely, this was primarily due to a reduction in the risk of ischemic stroke (2.4% vs 3.3% per year), approximately one third of which were not disabling. The risk of disabling stroke was lower with the combination therapy (1.6% vs 2.1% per year; P = .001; NNT = 200). There was no difference between groups regarding cardiovascular or all-cause mortality. Major hemorrhage was more common in the clopidogrel plus aspirin group (2.0% vs 1.3% per year; P < .001; NNTH = 143).